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ELISA addresses a critical bottleneck in single-cell genomics by creating an interpretable agent that bridges opaque expression embeddings with natural language queries for mechanistic discovery. This framework unifies scGPT and BioBERT components to perform tasks like pathway scoring and cell-type retrieval directly on embedded data, significantly outperforming classical lexical retrievers without needing raw count matrices. For the AI community, this represents a tangible step toward grounding large models in specific scientific domains where explainability is as vital as predictive accuracy.
ELISA: An Interpretable Hybrid Generative AI Agent for Expression-Grounded Discovery in Single-Cell Genomics
arXiv:2603.11872v3 Announce Type: replace-cross Abstract: Translating single-cell RNA sequencing (scRNA-seq) data into mechanistic biological hypotheses remains a critical bottleneck, as agentic AI systems lack direct access to transcriptomic representations while expression foundation models remain opaque to natural language. Here we introduce ELISA (Embedding-Linked Interactive Single-cell Agent), an interpretable framework that unifies scGPT expression embeddings with BioBERT-based semantic retrieval and LLM-mediated interpretation for interactive single-cell discovery. An automatic query classifier routes inputs to gene marker scoring, semantic matching, or reciprocal rank fusion pipelines depending on whether the query is a gene signature, natural language concept, or mixture of both. Integrated analytical modules perform pathway activity scoringacross 60+ gene sets, ligand-receptor interaction prediction using 280+ curated pairs, condition-aware comparative analysis, and cell-type proportion estimation all operating directly on embedded data without access to the original count matrix. Benchmarked across six diverse scRNA-seq datasets spanning inflammatory lung disease, pediatric and adult cancers, organoid models, healthy tissue, and neurodevelopment, ELISA significantly outperforms CellWhisperer, a classical lexical retriever (BM25), and a random baseline in cell type retrieval (combined permutation test, $p < 2\times10^{-5}$ for each), with particularly large gains on gene-signature queries (Cohen's $d = 5.98$ for MRR). ELISA replicates published biological findings (mean composite score 0.88), and generates candidate hypotheses through grounded LLM reasoning, bridging the gap between transcriptomic data exploration and biological discovery.
Abstract:Translating single-cell RNA sequencing (scRNA-seq) data into mechanistic biological hypotheses remains a critical bottleneck, as agentic AI systems lack direct access to transcriptomic representations while expression foundation models remain opaque to natural language. Here we introduce ELISA (Embedding-Linked Interactive Single-cell Agent), an interpretable framework that unifies scGPT expression embeddings with BioBERT-based semantic retrieval and LLM-mediated interpretation for interactive single-cell discovery. An automatic query classifier routes inputs to gene marker scoring, semantic matching, or reciprocal rank fusion pipelines depending on whether the query is a gene signature, natural language concept, or mixture of both. Integrated analytical modules perform pathway activity scoringacross 60+ gene sets, ligand-receptor interaction prediction using 280+ curated pairs, condition-aware comparative analysis, and cell-type proportion estimation all operating directly on embedded data without access to the original count matrix. Benchmarked across six diverse scRNA-seq datasets spanning inflammatory lung disease, pediatric and adult cancers, organoid models, healthy tissue, and neurodevelopment, ELISA significantly outperforms CellWhisperer, a classical lexical retriever (BM25), and a random baseline in cell type retrieval (combined permutation test, $p < 2\times10^{-5}$ for each), with particularly large gains on gene-signature queries (Cohen's $d = 5.98$ for MRR). ELISA replicates published biological findings (mean composite score 0.88), and generates candidate hypotheses through grounded LLM reasoning, bridging the gap between transcriptomic data exploration and biological discovery.
Genomics (q-bio.GN); Artificial Intelligence (cs.AI)
arXiv:2603.11872 [q-bio.GN]
(or arXiv:2603.11872v3 [q-bio.GN] for this version)
From: Omar Coser Mr. [view email] [v1] Thu, 12 Mar 2026 12:46:22 UTC (5,599 KB) [v2] Mon, 16 Mar 2026 18:08:47 UTC (5,599 KB) [v3] Fri, 31 Jul 2026 04:09:24 UTC (5,433 KB)
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